Methods and apparatus for treating end-stage renal disease

ABSTRACT

Methods and apparatus are provided for treating end-stage renal disease, e.g., via a pulsed electric field, via a stimulation electric field, via localized drug delivery, via high frequency ultrasound, via thermal techniques, etc. Such neuromodulation may effectuate irreversible electroporation or electrofusion, necrosis and/or inducement of apoptosis, alteration of gene expression, action potential attenuation or blockade, changes in cytokine up-regulation and other conditions in target neural fibers. In some embodiments, neuromodulation is applied to neural fibers that contribute to renal function. In some embodiments, such neuromodulation is performed in a bilateral fashion. Bilateral renal neuromodulation may provide enhanced therapeutic effect in some patients as compared to renal neuromodulation performed unilaterally, i.e., as compared to renal neuromodulation performed on neural tissue innervating a single kidney.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of each of thefollowing co-pending United States patent applications:

(1) U.S. patent application Ser. No. 10/408,665, filed on Apr. 8, 2003(published as U.S. Patent Publication 2003/0216792 on Nov. 20, 2003),which claims the benefit of U.S. Provisional Patent Application Nos.60/442,970, filed on Jan. 29, 2003; Ser. No. 60/415,575, filed on Oct.3, 2002; and 60/370,190, filed on Apr. 8, 2002.

(2) U.S. patent application Ser. No. 11/133,925, filed on May 20, 2005,which is a continuation of U.S. patent application Ser. No. 10/900,199,filed on Jul. 28, 2004 (now U.S. Pat. No. 6,978,174), which is acontinuation-in-part of U.S. patent application Ser. No. 10/408,665,filed on Apr. 8, 2003.

(3) U.S. patent application Ser. No. 11/189,563, filed on Jul. 25, 2005,which is a continuation-in-part of U.S. patent application Ser. No.11/129,765, filed on May 13, 2005, which claims the benefit of U.S.Provisional Patent Application Nos. 60/616,254, filed on Oct. 5, 2004;and 60/624,793, filed on Nov 2, 2004.

(4) U.S. patent application Ser. No. 11/266,933, filed on Nov. 4, 2005.

(5) U.S. patent application No. ______, filed on Feb. 27, 2006, entitledMethods and Apparatus for Pulsed Electric Field Neuromodulation Via anIntra-To-Extravascular Approach (Attorney Docket No. 57856.8010 US1),which (a) claims the benefit of U.S. Provisional Application No. ______,filed on Dec. 29, 2005, entitled Methods and Apparatus for PulsedElectric Field Neuromodulation Via an Intra-To-Extravascular Approach(Attorney Docket No. 57856.8010US and originally filed as U.S.application Ser. No. 11/324,188), and (b) is a continuation-in-part ofeach of U.S. patent application Ser. No. 11/189,563, filed on Jul. 25,2005, and U.S. patent application Ser. No. 11/266,933, filed on Nov. 4,2005.

All of the foregoing applications, publication and patent areincorporated herein by reference in their entireties.

Incorporation by Reference

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus forneuromodulation. In some embodiments, the present invention relates tomethods and apparatus for achieving bilateral renal neuromodulation.

BACKGROUND

Congestive Heart Failure (“CHF”) is a condition that occurs when theheart becomes damaged and reduces blood flow to the organs of the body.If blood flow decreases sufficiently, kidney function becomes altered,which results in fluid retention, abnormal hormone secretions andincreased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.Moreover, the fluid overload and associated clinical symptoms resultingfrom these physiologic changes result in additional hospital admissions,poor quality of life and additional costs to the health care system.

In addition to their role in the progression of CHF, the kidneys play asignificant role in the progression of Chronic Renal Failure (“CRF”),End-Stage Renal Disease (“ESRD”), hypertension (pathologically highblood pressure) and other cardio-renal diseases. The functions of thekidneys can be summarized under three broad categories: filtering bloodand excreting waste products generated by the body's metabolism;regulating salt, water, electrolyte and acid-base balance; and secretinghormones to maintain vital organ blood flow. Without properlyfunctioning kidneys, a patient will suffer water retention, reducedurine flow and an accumulation of waste toxins in the blood and body.These conditions result from reduced renal function or renal failure(kidney failure) and are believed to increase the workload of the heart.In a CHF patient, renal failure will cause the heart to furtherdeteriorate as fluids are retained and blood toxins accumulate due tothe poorly functioning kidneys.

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads todecreased removal of water and sodium from the body, as well asincreased renin secretion. Increased renin secretion leads tovasoconstriction of blood vessels supplying the kidneys which causesdecreased renal blood flow. Reduction of sympathetic renal nerveactivity, e.g., via denervation, may reverse these processes.

Applicants have previously described methods and apparatus for treatingrenal disorders by applying a pulsed electric field to neural fibersthat contribute to renal function. See, for example, Applicants'co-pending U.S. patent application Ser. No. 11/129,765, filed on May 13,2005, and Ser. No. 11/189,563, filed on Jul. 25, 2005, both of which areincorporated herein by reference in their entireties. A pulsed electricfield (“PEF”) may initiate renal neuromodulation, e.g., denervation, forexample, via irreversible electroporation or via electrofusion. The PEFmay be delivered from apparatus positioned intravascularly,extravascularly, intra-to-extravascularly or a combination thereof.Additional methods and apparatus for achieving renal neuromodulation,e.g., via localized drug delivery (such as by a drug pump or infusioncatheter) or via use of a stimulation electric field, etc, aredescribed, for example, in co-owned and co-pending U.S. patentapplication Ser. No. 10/408,665, filed Apr. 8, 2003, and U.S. Pat. No.6,978,174, both of which are incorporated herein by reference in theirentireties.

As used herein, electrofusion comprises fusion of neighboring cellsinduced by exposure to an electric field. Contact between targetneighboring cells for the purposes of electrofusion may be achieved in avariety of ways, including, for example, via dielectrophoresis. Intissue, the target cells may already be in contact, thus facilitatingelectrofusion.

As used herein, electroporation and electropermeabilization are methodsof manipulating the cell membrane or intracellular apparatus. Forexample, the porosity of a cell membrane may be increased by inducing asufficient voltage across the cell membrane through, e.g., short,high-voltage pulses. The extent of porosity in the cell membrane (e.g.,size and number of pores) and the duration of effect (e.g., temporary orpermanent) are a function of multiple variables, such as field strength,pulse width, duty cycle, electric field orientation, cell type or sizeand/or other parameters.

Cell membrane pores will generally close spontaneously upon terminationof relatively lower strength electric fields or relatively shorter pulsewidths (herein defined as “reversible electroporation”). However, eachcell or cell type has a critical threshold above which pores do notclose such that pore formation is no longer reversible; this result isdefined as “irreversible electroporation,” “irreversible breakdown” or“irreversible damage.” At this point, the cell membrane ruptures and/orirreversible chemical imbalances caused by the high porosity occur. Suchhigh porosity can be the result of a single large hole and/or aplurality of smaller holes.

A potential challenge of using intravascular PEF systems for treatingrenal disorders is to selectively electroporate target cells withoutaffecting other cells. For example, it may be desirable to irreversiblyelectroporate renal nerve cells that travel along or in proximity torenal vasculature, but it may not be desirable to damage the smoothmuscle cells of which the vasculature is composed. As a result, anoverly aggressive course of PEF therapy may persistently injure therenal vasculature, but an overly conservative course of PEF therapy maynot achieve the desired renal neuromodulation.

Applicants have previously described methods and apparatus formonitoring tissue impedance or conductivity to determine the effects ofpulsed electric field therapy, e.g., to determine an extent ofelectroporation and/or its degree of irreversibility. See, for example,Applicant's co-pending U.S. patent application Ser. No. 11/233,814,filed Sep. 23, 2005, which is incorporated herein by reference in itsentirety. Pulsed electric field electroporation of tissue causes adecrease in tissue impedance and an increase in tissue conductivity. Ifinduced electroporation is reversible, tissue impedance and conductivityshould approximate baseline levels upon cessation of the pulsed electricfield. However, if electroporation is irreversible, impedance andconductivity changes should persist after terminating the pulsedelectric field. Thus, monitoring the impedance or conductivity of targetand/or non-target tissue may be utilized to determine the onset ofelectroporation and to determine the type or extent of electroporation.Furthermore, monitoring data may be used in one or more manual orautomatic feedback loops to control the electroporation.

It would be desirable to provide methods and apparatus for achievingbilateral renal neuromodulation.

SUMMARY

The present invention provides methods and apparatus forneuromodulation, e.g., via a pulsed electric field (“PEF”), via astimulation electric field, via localized drug delivery, via highfrequency ultrasound, via thermal techniques, combinations thereof, etc.Such neuromodulation may, for example, effectuate irreversibleelectroporation or electrofusion, necrosis and/or inducement ofapoptosis, alteration of gene expression, action potential blockade orattenuation, changes in cytokine up-regulation and other conditions intarget neural fibers. In some patients, when the neuromodulatory methodsand apparatus of the present invention are applied to renal nervesand/or other neural fibers that contribute to renal neural functions,applicants believe that the neuromodulatory effects induced by theneuromodulation might result in increased urine output, decreased plasmarenin levels, decreased tissue (e.g., kidney) and/or urinecatecholamines (e.g., norepinephrine), increased urinary sodiumexcretion, and/or controlled blood pressure. Furthermore, applicantsbelieve that these or other changes might prevent or treat congestiveheart failure, hypertension, acute myocardial infarction, end-stagerenal disease, contrast nephropathy, other renal system diseases, and/orother renal or cardio-renal anomalies. The methods and apparatusdescribed herein could be used to modulate efferent or afferent nervesignals, as well as combinations of efferent and afferent nerve signals.

Renal neuromodulation preferably is performed in a bilateral fashion,such that neural fibers contributing to renal function of both the rightand left kidneys are modulated. Bilateral renal neuromodulation mayprovide enhanced therapeutic effect in some patients as compared torenal neuromodulation performed unilaterally, i.e., as compared to renalneuromodulation performed on neural tissue innervating a single kidney.In some embodiments, concurrent modulation of neural fibers thatcontribute to both right and left renal function may be achieved. Inadditional or alternative embodiments, such modulation of the right andleft neural fibers may be sequential. Bilateral renal neuromodulationmay be continuous or intermittent, as desired.

When utilizing an electric field, the electric field parameters may bealtered and combined in any combination, as desired. Such parameters caninclude, but are not limited to, voltage, field strength, pulse width,pulse duration, the shape of the pulse, the number of pulses and/or theinterval between pulses (e.g., duty cycle), etc. For example, whenutilizing a pulsed electric field, suitable field strengths can be up toabout 10,000 V/cm and suitable pulse widths can be up to about 1 second.Suitable shapes of the pulse waveform include, for example, ACwaveforms, sinusoidal waves, cosine waves, combinations of sine andcosine waves, DC waveforms, DC-shifted AC waveforms, RF waveforms,square waves, trapezoidal waves, exponentially-decaying waves, orcombinations. The field includes at least one pulse, and in manyapplications the field includes a plurality of pulses. Suitable pulseintervals include, for example, intervals less than about 10 seconds.These parameters are provided as suitable examples and in no way shouldbe considered limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken inconjunction with the accompanying drawings, in which like referencecharacters refer to like parts throughout, and in which:

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic isometric detail view showing the location of therenal nerves relative to the renal artery.

FIGS. 3A and 3B are schematic isometric and end views, respectively,illustrating orienting of an electric field for selectively affectingrenal nerves.

FIG. 4 is a schematic side view, partially in section, illustrating anexample of an extravascular method and apparatus for renalneuromodulation.

FIGS. 5A and 5B are schematic side views, partially in section,illustrating examples of, respectively, intravascular andintra-to-extravascular methods and apparatus for renal neuromodulation.

FIGS. 6A-6H are schematic side views, partially in section, illustratingmethods of achieving bilateral renal neuromodulation utilizing apparatusof the present invention, illustratively utilizing the apparatus of FIG.5A.

FIGS. 7A and 7B are schematic side views, partially in section,illustrating methods of achieving concurrent bilateral renalneuromodulation utilizing embodiments of the apparatus of FIG. 5A.

FIG. 8 is a schematic side view, partially in section, illustratingmethods of achieving concurrent bilateral renal neuromodulationutilizing an alternative embodiment of the apparatus of FIG. 4.

FIG. 9 is a schematic view illustrating an example of methods andapparatus for achieving bilateral renal neuromodulation via localizeddrug delivery.

DETAILED DESCRIPTION

A. Overview

The present invention relates to methods and apparatus forneuromodulation, e.g., denervation. In some embodiments, the presentinvention provides methods and apparatus for achieving bilateral renalneuromodulation. Bilateral renal neuromodulation may provide enhancedtherapeutic effect in some patients as compared to renal neuromodulationperformed unilaterally, i.e., as compared to renal neuromodulationperformed on neural tissue innervating a single kidney. In someembodiments, concurrent modulation of neural fibers that contribute toboth right and left renal function may be achieved. In additional oralternative embodiments, such modulation of the right and left neuralfibers may be sequential. Bilateral renal neuromodulation may becontinuous or intermittent, as desired.

The methods and apparatus of the present invention may be used tomodulate neural fibers that contribute to renal function and may exploitany suitable neuromodulatory techniques that will achieve the desiredneuromodulation. For example, any suitable electrical signal or fieldparameters, e.g., any electric field that will achieve the desiredneuromodulation (e.g., electroporative effect) may be utilized.Alternatively or additionally, neuromodulation may be achieved vialocalized delivery of a neuromodulatory agent or drug. To betterunderstand the structures of devices of the present invention and themethods of using such devices for bilateral renal neuromodulation, it isinstructive to examine the renal anatomy in humans.

B. Selected Embodiments of Methods for Neuromodulation

With reference now to FIG. 1, the human renal anatomy includes kidneys Kthat are supplied with oxygenated blood by renal arteries RA, which areconnected to the heart by the abdominal aorta AA. Deoxygenated bloodflows from the kidneys to the heart via renal veins RV and the inferiorvena cava IVC. FIG. 2 illustrates a portion of the renal anatomy ingreater detail. More specifically, the renal anatomy also includes renalnerves RN extending longitudinally along the lengthwise dimension L ofrenal artery RA generally within the adventitia of the artery. The renalartery RA has smooth muscle cells SMC that surround the arterialcircumference and spiral around the angular axis θ of the artery. Thesmooth muscle cells of the renal artery accordingly have a lengthwise orlonger dimension extending transverse (i.e., non-parallel) to thelengthwise dimension of the renal artery. The misalignment of thelengthwise dimensions of the renal nerves and the smooth muscle cells isdefined as “cellular misalignment.”

Referring to FIGS. 3A and 3B, the cellular misalignment of the renalnerves and the smooth muscle cells may be. exploited to selectivelyaffect renal nerve cells with reduced effect on smooth muscle cells.More specifically, because larger cells require a lower electric fieldstrength to exceed the cell membrane irreversibility threshold voltageor energy for irreversible electroporation, embodiments of electrodes ofthe present invention may be configured to align at least a portion ofan electric field generated by the electrodes with or near the longerdimensions of the cells to be affected. In specific embodiments, thedevice has electrodes configured to create an electrical field alignedwith or near the lengthwise dimension L of the renal artery RA to affectrenal nerves RN. By aligning an electric field so that the fieldpreferentially aligns with the lengthwise aspect of the cell rather thanthe diametric or radial aspect of the cell, lower field strengths may beused to affect target neural cells, e.g., to necrose or fuse the targetcells, to induce apoptosis, to alter gene expression, to attenuate orblock action potentials, to change cytokine up-regulation and/or toinduce other suitable processes. This is expected to reduce total energydelivered to the system and to mitigate effects on non-target cells inthe electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying orunderlying the target nerve are orthogonal or otherwise off-axis (e.g.,transverse) with respect to the longer dimensions of the nerve cells.Thus, in addition to aligning a pulsed electric field (“PEF”) with thelengthwise or longer dimensions of the target cells, the PEF maypropagate along the lateral or shorter dimensions of the non-targetcells (i.e., such that the PEF propagates at least partially out ofalignment with non-target smooth muscle cells SMC). Therefore, as seenin FIGS. 3A and 3B, applying a PEF with propagation lines Li generallyaligned with the longitudinal dimension L of the renal artery RA isexpected to preferentially cause electroporation (e.g., irreversibleelectroporation), electrofusion or other neuromodulation in cells of thetarget renal nerves RN without unduly affecting the non-target arterialsmooth muscle cells SMC. The pulsed electric field may propagate in asingle plane along the longitudinal axis of the renal artery, or maypropagate in the longitudinal direction along any angular segment θthrough a range of 0 °-360 °.

A PEF system placed within and/or in proximity to the wall of the renalartery may propagate an electric field having a longitudinal portionthat is aligned to run with the longitudinal dimension of the artery inthe region of the renal nerves RN and the smooth muscle cells SMC of thevessel wall so that the wall of the artery remains at leastsubstantially intact while the outer nerve cells are destroyed, fused orotherwise affected. Monitoring elements may be utilized to assess anextent of, e.g., electroporation, induced in renal nerves and/or insmooth muscle cells, as well as to adjust PEF parameters to achieve adesired effect.

C. Exemplary Embodiments of Systems and Additional Methods forNeuromodulation

With reference to FIGS. 4 and 5, examples of PEF systems and methods aredescribed. FIG. 4 shows one embodiment of an extravascular pulsedelectric field apparatus 200 that includes one or more electrodesconfigured to deliver a pulsed electric field to renal neural fibers toachieve renal neuromodulation. The apparatus of FIG. 4 is configured fortemporary extravascular placement; however, it should be understood thatpartially or completely implantable extravascular apparatus additionallyor alternatively may be utilized. Applicants have previously describedextravascular PEF systems, for example, in co-pending U.S. patentapplication Ser. No. 11/189,563, filed Jul. 25, 2005, which has beenincorporated herein by reference in its entirety.

In FIG. 4, apparatus 200 comprises a laparoscopic or percutaneous PEFsystem having a probe 210 configured for insertion in proximity to thetrack of the renal neural supply along the renal artery or vein or hilumand/or within Gerota's fascia under, e.g., CT or radiographic guidance.At least one electrode 212 is configured for delivery through the probe210 to a treatment site for delivery of pulsed electric field therapy.The electrode(s) 212, for example, may be mounted on a catheter andelectrically coupled to a pulse generator 50 via wires 211. In analternative embodiment, a distal section of the probe 210 may have oneelectrode 212, and the probe may have an electrical connector to couplethe probe to the pulse generator 50 for delivering a PEF to theelectrode(s) 212.

The pulsed electric field generator 50 is located external to thepatient. The generator, as well as any of the PEF-delivery electrodeembodiments described herein, may be utilized with any embodiment of thepresent invention for delivery of a PEF with desired field parameters.It should be understood that PEF-delivery electrodes of embodimentsdescribed hereinafter may be electrically connected to the generatoreven though the generator is not explicitly shown or described with eachembodiment.

The electrode(s) 212 can be individual electrodes that are electricallyindependent of each other, a segmented electrode with commonly connectedcontacts, or a continuous electrode. A segmented electrode may, forexample, be formed by providing a slotted tube fitted onto theelectrode, or by electrically connecting a series of individualelectrodes. Individual electrodes or groups of electrodes 212 may beconfigured to provide a bipolar signal. The electrodes 212 may bedynamically assignable to facilitate monopolar and/or bipolar energydelivery between any of the electrodes and/or between any of theelectrodes and an external ground pad. Such a ground pad may, forexample, be attached externally to the patient's skin, e.g., to thepatient's leg or flank. In FIG. 4, the electrodes 212 comprise a bipolarelectrode pair. The probe 210 and the electrodes 212 may be similar tothe standard needle or trocar-type used clinically for pulsed RF nerveblock. Alternatively, the apparatus 200 may comprise a flexible and/orcustom-designed probe for the renal application described herein.

In FIG. 4, the percutaneous probe 210 has been advanced through apercutaneous access site P into proximity with a patient's renal arteryRA. The probe pierces the patient's Gerota's fascia F, and theelectrodes 212 are advanced into position through the probe and alongthe annular space between the patient's artery and fascia. Once properlypositioned, pulsed electric field therapy may be applied to targetneural fibers across the bipolar electrodes 212. Such PEF therapy may,for example, at least partially denervate the kidney innervated by thetarget neural fibers through irreversible electroporation of cells ofthe target neural fibers. The electrodes 212 optionally also may be usedto monitor the electroporative effects of the PEF therapy. Aftertreatment, the apparatus 200 may be removed from the patient to concludethe procedure.

Referring now to FIG. 5A, an embodiment of an intravascular PEF systemis described. Applicants have previously described intravascular PEFsystems, for example, in co-pending U.S. patent application Ser. No.11/129,765, filed May 13, 2005, which has been incorporated herein byreference in its entirety. The embodiment of FIG. 5A includes anapparatus 300 comprising a catheter 302 having a centering element 304(e.g., a balloon, an expandable wire basket, other mechanical expanders,etc.), shaft electrodes 306 a and 306 b disposed along the shaft of thecatheter, and optional radiopaque markers 308 disposed along the shaftof the catheter in the region of the centering element 304. Theelectrodes 306 a-b, for example, can be arranged such that the electrode306 a is near a proximal end of the centering element 304 and theelectrode 306 b is near the distal end of the centering element 304. Theelectrodes 306 are electrically coupled to the pulse generator 50 (seeFIG. 4), which is disposed external to the patient, for delivery of thePEF therapy.

The centering element 304 may comprise an impedance-altering elementthat alters the impedance between electrodes 306 a and 306 b during thePEF therapy, for example, to better direct the PEF therapy across thevessel wall. This may reduce an applied voltage required to achievedesired renal neuromodulation. Applicants have previously described useof an impedance-altering element, for example, in co-pending U.S. patentapplication Ser. No. 11/266,993, filed Nov. 4, 2005, which isincorporated herein by reference in its entirety. When the centeringelement 304 comprises an inflatable balloon, the balloon may serve asboth the centering element for the electrodes 306 and as animpedance-altering electrical insulator for directing an electric fielddelivered across the electrodes, e.g., for directing the electric fieldinto or across the vessel wall for modulation of target neural fibers.Electrical insulation provided by the element 304 may reduce themagnitude of applied voltage or other parameters of the pulsed electricfield necessary to achieve desired field strength at the target fibers.

The electrodes 306 can be individual electrodes (i.e., independentcontacts), a segmented electrode with commonly connected contacts, or asingle continuous electrode. Furthermore, the electrodes 306 may beconfigured to provide a bipolar signal, or the electrodes 306 may beused together or individually in conjunction with a separate patientground pad for monopolar use. As an alternative or in addition toplacement of the electrodes 306 along the central shaft of catheter 302,as in FIG. 5A, the electrodes 306 may be attached to the centeringelement 304 such that they contact the wall of the renal artery RA. Insuch a variation, the electrodes may, for example, be affixed to theinside surface, outside surface or at least partially embedded withinthe wall of the centering element. The electrodes optionally may be usedto monitor the effects of PEF therapy, as described hereinafter. As itmay be desirable to reduce or minimize physical contact between thePEF-delivery electrodes and the vessel wall during delivery of PEFtherapy, e.g., to reduce the potential for injuring the wall, theelectrodes 306 may, for example, comprise a first set of electrodesattached to the shaft of the catheter for delivering the PEF therapy,and the device may further include a second set of electrodes optionallyattached to the centering element 304 for monitoring the effects of PEFtherapy delivered via the electrodes 306.

In use, the catheter 302 may be delivered to the renal artery RA asshown, or it may be delivered to a renal vein or to any other vessel inproximity to neural tissue contributing to renal function, in a lowprofile delivery configuration, for example, through a guide catheter.Once positioned within the renal vasculature, the optional centeringelement 304 may be expanded into contact with an interior wall of thevessel. A pulsed electric field then may be generated by the PEFgenerator 50, transferred through the catheter 302 to the electrodes306, and delivered via the electrodes 306 across the wall of the artery.The PEF therapy modulates the activity along neural fibers thatcontribute to renal function, e.g., at least partially denervates thekidney innervated by the neural fibers. This may be achieved, forexample, via irreversible electroporation, electrofusion and/orinducement of apoptosis in the nerve cells. In many applications, theelectrodes are arranged so that the pulsed electric field is alignedwith the longitudinal dimension of the renal artery to facilitatemodulation of renal nerves with little effect on non-target smoothmuscle cells or other cells.

In addition to extravascular and intravascular PEF systems,intra-to-extravascular PEF systems may be provided having electrode(s)that are delivered to an intravascular position, then at least partiallypassed through/across the vessel wall to an extravascular position priorto delivery of PEF therapy. Intra-to-extravascular positioning of theelectrode(s) may place the electrode(s) in closer proximity to targetneural fibers during the PEF therapy compared to fully intravascularpositioning of the electrode(s). Applicants have previously describedintra-to-extravascular PEF systems, for example, in co-pending U.S.patent application Ser. No. 11/324,188 (hereinafter, “the ′188application”), filed Dec. 29, 2005, which is incorporated herein byreference in its entirety.

With reference to FIG. 5B, one embodiment of an intra-to-extravascular(“ITEV”) PEF system, described previously in the ′188 application, isshown. ITEV PEF system 320 comprises a catheter 322 having (a) aplurality of proximal electrode lumens terminating at proximal sideports 324, (b) a plurality of distal electrode lumens terminating atdistal side ports 326, and (c) a guidewire lumen 323. The catheter 322preferably comprises an equal number of proximal and distal electrodelumens and side ports. The system 320 also includes proximal needleelectrodes 328 that may be advanced through the proximal electrodelumens and the proximal side ports 324, as well as distal needleelectrodes 329 that may be advanced through the distal electrode lumensand the distal side ports 326.

Catheter 322 comprises an optional expandable centering element 330,which may comprise an inflatable balloon or an expandable basket orcage. In use, the centering element 330 may be expanded prior todeployment of the needle electrodes 328 and 329 in order to center thecatheter 322 within the patient's vessel (e.g., within renal artery RA).Centering the catheter 322 is expected to facilitate delivery of allneedle electrodes to desired depths within/external to the patient'svessel (e.g., to deliver all of the needle electrodes approximately tothe same depth). In FIG. 5B, the illustrated centering element 330 ispositioned between the proximal side ports 324 and the distal side ports326, i.e., between the delivery positions of the proximal and distalelectrodes. However, it should be understood that centering element 330additionally or alternatively may be positioned at a different locationor at multiple locations along the length of the catheter 322 (e.g., ata location proximal of the side ports 324 and/or at a location distal ofthe side ports 326).

As illustrated in FIG. 5B, the catheter 322 may be advanced to atreatment site within the patient's vasculature (e.g., to a treatmentsite within the patient's renal artery RA) over a guidewire (not shown)via the lumen 323. During intravascular delivery, the electrodes 328 and329 may be positioned such that their non-insulated and sharpened distalregions are positioned within the proximal and distal lumens,respectively. Once positioned at a treatment site, a medicalpractitioner may advance the electrodes via their proximal regions thatare located external to the patient. Such advancement causes the distalregions of the electrodes 328 and 329 to exit side ports 324 and 326,respectively, and pierce the wall of the patient's vasculature such thatthe electrodes are positioned extravascularly via an ITEV approach.

The proximal electrodes 328 can be connected to PEF generator 50 asactive electrodes and the distal electrodes 329 can serve as returnelectrodes. In this manner, the proximal and distal electrodes formbipolar electrode pairs that align PEF therapy with a longitudinal axisor direction of the patient's vasculature. As will be apparent, thedistal electrodes 329 alternatively may comprise the active electrodesand the proximal electrodes 328 may comprise the return electrodes.Furthermore, the proximal and/or the distal electrodes may comprise bothactive and return electrodes. Any combination of active and distalelectrodes may be utilized, as desired.

When the electrodes 328 and 329 are connected to PEF generator 50 andare positioned extravascularly, and with centering element 330optionally expanded, PEF therapy may proceed to achieve desiredneuromodulation. After completion of the PEF therapy, the electrodes maybe retracted within the proximal and distal lumens, and centeringelement 330 may be collapsed for retrieval. ITEV PEF system 320 then maybe removed from the patient to complete the procedure. Additionally oralternatively, the system may be repositioned to provide PEF therapy atanother treatment site, for example, to provide bilateral renalneuromodulation.

It is expected that PEF therapy, as well as other methods and apparatusof the present invention for neuromodulation (e.g., stimulation electricfields, localized drug delivery, high frequency ultrasound, thermaltechniques, etc.), whether delivered extravascularly, intravascularly,intra-to-extravascularly or a combination thereof, may, for example,effectuate irreversible electroporation or electrofusion, necrosisand/or inducement of apoptosis,. alteration of gene expression, actionpotential blockade or attenuation, changes in cytokine up-regulation andother conditions in target neural fibers. In some patients, when suchneuromodulatory methods and apparatus are applied to renal nerves and/orother neural fibers that contribute to renal neural functions,applicants believe that the neuromodulatory effects induced by theneuromodulation might result in increased urine output, decreased plasmarenin levels, decreased tissue (e.g., kidney) and/or urinecatecholamines (e.g., norepinephrine), increased urinary sodiumexcretion, and/or controlled blood pressure. Furthermore, applicantsbelieve that these or other changes might prevent or treat congestiveheart failure, hypertension, acute myocardial infarction, end-stagerenal disease, contrast nephropathy, other renal system diseases, and/orother renal or cardio-renal anomalies for a period of months,potentially up to six months or more. This time period may be sufficientto allow the body to heal; for example, this period may reduce the riskof CHF onset after an acute myocardial infarction, thereby alleviating aneed for subsequent re-treatment. Alternatively, as symptoms reoccur, orat regularly scheduled intervals, the patient may return to thephysician for a repeat therapy. The methods and apparatus describedherein could be used to modulate efferent or afferent nerve signals, aswell as combinations of efferent and afferent nerve signals.Neuromodulation in accordance with the present invention preferably isachieved without completely physically severing, i.e., without fullycutting, the target neural fibers. However, it should be understood thatsuch neuromodulation may functionally sever the neural fibers, eventhough the fibers may not be completely physically severed. Apparatusand methods described herein illustratively are configured forpercutaneous use. Such percutaneous use may be endoluminal,laparoscopic, a combination thereof, etc.

The apparatus described above with respect to FIGS. 4 and 5 additionallymay be used to quantify the efficacy, extent or cell selectivity of PEFtherapy to monitor and/or control the therapy. When a pulsed electricfield initiates electroporation, the impedance of the electroporatedtissue begins to decrease and the conductivity of the tissue begins toincrease. If the electroporation is reversible, the tissue electricalparameters will return or approximate baseline values upon cessation ofthe PEF. However, if the electroporation is irreversible, the changes intissue parameters will persist after termination of the PEF. Thesephenomena may be utilized to monitor both the onset and the effects ofPEF therapy. For example, electroporation may be monitored directlyusing, for example, conductivity measurements or impedance measurements,such as Electrical Impedance Tomography (“EIT”) and/or other electricalimpedance/conductivity measurements like an electrical impedance orconductivity index. Such electroporation monitoring data optionally maybe used in one or more feedback loops to control delivery of PEFtherapy.

In order to collect the desired monitoring data, additional monitoringelectrodes optionally may be provided in proximity to the monitoredtissue. The distance between such monitoring electrodes preferably wouldbe specified prior to therapy delivery and used to determineconductivity from impedance or conductance measurements. For thepurposes of the present invention, the imaginary part of impedance maybe ignored such that impedance is defined as voltage divided by current,while conductance may be defined as the inverse of impedance (i.e.,current divided by voltage), and conductivity may be defined asconductance per unit distance. Applicants have previously describedmethods and apparatus for monitoring PEF therapy, as well as exemplaryPEF waveforms, in co-pending U.S. patent application Ser. No.11/233,814, filed September 23, 2005, which has been incorporated hereinby reference in its entirety.

Although the embodiments of FIGS. 4 and 5 illustratively comprisebipolar apparatus, it should be understood that monopolar apparatusalternatively may be utilized. For example, an active monopolarelectrode may be positioned intravascularly, extravascularly orintra-to-extravascularly in proximity to target neural fibers thatcontribute to renal function. A return electrode ground pad may beattached to the exterior of the patient. Finally, PEF therapy may bedelivered between to the in vivo monopolar electrode and the ground padto effectuate desired renal neuromodulation. Monopolar apparatusadditionally may be utilized for bilateral renal neuromodulation.

It may be desirable to achieve bilateral renal neuromodulation.Bilateral neuromodulation may enhance the therapeutic effect in somepatients as compared to renal neuromodulation performed unilaterally,i.e., as compared to renal neuromodulation performed on neural tissueinnervating a single kidney. For example, bilateral renalneuromodulation may further reduce clinical symptoms of CHF,hypertension, acute myocardial infarction, contrast nephropathy, renaldisease and/or other cardio-renal diseases. FIGS. 6A-6H illustratestages of a method for bilateral renal neuromodulation utilizing theintravascular apparatus of FIG. 5A. However, it should be understoodthat such bilateral neuromodulation alternatively may be achievedutilizing the extravascular apparatus of FIG. 4, utilizing theintra-to-extravascular apparatus of FIG. 5B, or utilizing anyalternative intravascular apparatus, extravascular apparatus,intra-to-extravascular apparatus (including monopolar apparatus) orcombination thereof.

As seen in FIGS. 6A and 6E, a guide catheter GC and a guidewire G may beadvanced into position within, or in proximity to, either the patient'sleft renal artery LRA or right renal artery RRA. In FIG. 6A, theguidewire illustratively has been positioned in the right renal arteryRRA, but it should be understood that the order of bilateral renalneuromodulation illustrated in FIGS. 6A-6H alternatively may bereversed. Additionally or alternatively, bilateral renal neuromodulationmay be performed concurrently on both right and left neural fibers thatcontribute to renal function, as in FIGS. 7-9, rather than sequentially,as in FIGS. 6.

With the guidewire and the guide catheter positioned in the right renalartery, the catheter 302 of the apparatus 300 may be advanced over theguidewire and through the guide catheter into position within theartery. As seen in FIG. 6B, the optional centering element 304 of thecatheter 302 is in a reduced delivery configuration during delivery ofthe catheter to the renal artery. In FIG. 6C, once the catheter isproperly positioned for PEF therapy, the element 304 optionally may beexpanded into contact with the vessel wall, and the guidewire G may beretracted from the treatment zone, e.g., may be removed from the patientor may be positioned more proximally within the patient's aorta.

Expansion of element 304 may center the electrodes 306 within the vesseland/or may alter impedance between the electrodes. With apparatus 300positioned and deployed as desired, PEF therapy may be delivered in abipolar fashion across the electrodes 306 to achieve renalneuromodulation in neural fibers that contribute to right renalfunction, e.g., to at least partially achieve renal denervation of theright kidney. As illustrated by propagation lines Li, the pulsedelectric field may be aligned with a longitudinal dimension of the renalartery RA and may pass across the vessel wall. The alignment andpropagation path of the pulsed electric field is expected topreferentially modulate cells of the target renal nerves without undulyaffecting non-target arterial smooth muscle cells.

As seen in FIG. 6D, after completion of the PEF therapy, the element 304may be collapsed back to the reduced delivery profile, and the catheter302 may be retracted from the right renal artery RRA, for example, to aposition in the guide catheter GC within the patient's abdominal aorta.Likewise, the guide catheter GC may be retracted to a position withinthe patient's aorta. The retracted guide catheter may be repositioned,e.g., rotated, such that its distal outlet is generally aligned with theleft renal artery LRA. The guidewire G then may be re-advanced throughthe catheter 302 and the guide catheter GC to a position within the leftrenal artery LRA, as shown in FIG. 6E (as will be apparent, the order ofadvancement of the guidewire and the guide catheter optionally may bereversed when accessing either renal artery).

Next, the catheter 302 may be re-advanced over the guidewire and throughthe guide catheter into position within the left renal artery, as shownin FIG. 6F. In FIG. 6G, once the catheter is properly positioned for PEFtherapy, the element 304 optionally may be expanded into contact withthe vessel wall, and the guidewire G may be retracted to a positionproximal of the treatment site. PEF therapy then may be delivered in abipolar fashion across the electrodes 306, for example, alongpropagation lines Li, to achieve renal neuromodulation in neural fibersthat contribute to left renal function, e.g., to at least partiallyachieve renal denervation of the left kidney. As seen in FIG. 6H, aftercompletion of the bilateral PEF therapy, the element 304 may becollapsed back to the reduced delivery profile, and the catheter 302, aswell as the guidewire G and the guide catheter GC, may be removed fromthe patient to complete the bilateral renal neuromodulation procedure.

As discussed previously, bilateral renal neuromodulation optionally maybe performed concurrently on fibers that contribute to both right andleft renal function. FIGS. 7A and 7B illustrate embodiments of apparatus300 for performing concurrent bilateral renal neuromodulation. In theembodiment of FIG. 7A, apparatus 300 comprises dual PEF therapycatheters 302, as well as dual guidewires G and guide catheters GC. Onecatheter 302 is positioned within the right renal artery RRA, and theother catheter 302 is positioned within the left renal artery LRA. Withcatheters 302 positioned in both the right and left renal arteries, PEFtherapy may be delivered concurrently by the catheters 302 to achieveconcurrent bilateral renal neuromodulation, illustratively via anintravascular approach.

In one example, separate arteriotomy sites may be made in the patient'sright and left femoral arteries for percutaneous delivery of the twocatheters 302. Alternatively, both catheters 302 may be deliveredthrough a single femoral access site, either through dual guidecatheters or through a single guide catheter. FIG. 7B illustrates anexample of apparatus 300 for concurrent bilateral renal neuromodulationutilizing a single arteriotomy access site. In the example of FIG. 7B,both catheters 302 are delivered through a custom bifurcated guidecatheter GC'having a bifurcated distal region for concurrentlydelivering the catheters 302 to the right and left renal arteries.Concurrent (or sequential) bilateral PEF therapy then may proceed.

FIG. 8 illustrates additional methods and apparatus for concurrentbilateral renal neuromodulation. In FIG. 8, an embodiment ofextravascular apparatus 200 comprising dual probes 210 and electrodes212. The electrodes have been positioned in the vicinity of both theleft renal artery LRA and the right renal artery RRA. PEF therapy may bedelivered concurrently by the electrodes 212 to achieve concurrentbilateral renal neuromodulation, illustratively via an extravascularapproach.

As will be apparent, intra-to-extravascular apparatus alternatively maybe utilized for bilateral renal neuromodulation. Such bilateral renalneuromodulation may be performed sequentially, concurrently or acombination thereof. For example, ITEV PEF system 320 of FIG. 5B may beutilized for bilateral renal neuromodulation.

Additional methods and apparatus for achieving renal neuromodulation,e.g., via localized drug delivery (such as by a drug pump or infusioncatheter) or via use of a stimulation electric field, etc, also mayutilized. Examples of such methods and apparatus have been describedpreviously, for example, in co-owned and co-pending United States patentapplication Ser. No. 10/408,665, filed Apr. 8, 2003, and in U.S. Pat.No. 6,978,174, both of which have been incorporated herein by referencein their entireties.

FIG. 9 shows one example of methods and apparatus for achievingbilateral renal neuromodulation via localized drug delivery. In FIG. 9,drug reservoir 400, illustratively an implantable drug pump, has beenimplanted within the patient. Drug delivery catheters 402 a and 402 bare connected to the drug reservoir and extend to the vicinity of theright renal artery RRA and the left renal artery LRA, respectively, fordelivery of one or more neuromodulatory agents or drugs capable ofmodulating neural fibers that contribute renal function. Delivering theagent(s) through catheters 402 a and 402 b may achieve bilateral renalneuromodulation. Such drug delivery through catheters 402 a and 402 bmay be conducted concurrently or sequentially, as well as continuouslyor intermittently, as desired, in order to provide concurrent orsequential, continuous or intermittent, renal neuromodulation,respectively.

In an alternative embodiment of the apparatus of FIG. 9, catheters 402 aand 402 b may only temporarily be positioned at a desired location,e.g., for acute delivery of the neuromodulatory agent(s) from anexternal drug reservoir, such as a syringe. Such temporary positioningmay comprise, for example, intravascular, extravascular and/orintra-to-extravascular placement of the catheters. In anotheralternative embodiment, the drug reservoir 400 may be replaced with animplantable neurostimulator or a pacemaker-type device, and catheters402 may be replaced with electrical leads coupled to the neurostimulatorfor delivery of an electric field, such as a pulsed electric field or astimulation electric field, to the target neural fibers. In yet anotheralternative embodiment, electrical techniques may be combined withdelivery of neuromodulatory agent(s) to achieve desired bilateral renalneuromodulation.

Although preferred illustrative variations of the present invention aredescribed above, it will be apparent to those skilled in the art thatvarious changes and modifications may be made thereto without departingfrom the invention. For example, although the variations primarily havebeen described for use in combination with pulsed electric fields, itshould be understood that any other electric field may be delivered asdesired, including stimulation or nerve block electric fields, and anyother alternative neuromodulatory techniques, such as localized deliveryof a neuromodulatory agent or drug, may be utilized. It is intended inthe appended claims to cover all such changes and modifications thatfall within the true spirit and scope of the invention.

1. A method for treating end-stage renal disease, the method comprising:modulating a function of a neural fiber that contributes to renalfunction of a kidney of a patient, wherein modulating the function ofthe neural fiber further comprises modulating the function withoutcompletely physically severing the neural fiber.
 2. The method of claim1, wherein modulating the function of the neural fiber further comprisesmodulating the function of the neural fiber via an electric field. 3.The method of claim 2, wherein modulating the function of the neuralfiber via an electric field further comprises exposing the neural fiberto a pulsed electric field.
 4. The method of claim 2, wherein modulatingthe function of the neural fiber via an electric field further comprisesexposing the neural fiber to a stimulation electric field.
 5. The methodof claim 1, wherein modulating the function of the neural fiber furthercomprises delivering a neuromodulatory agent to the neural fiber.
 6. Themethod of claim 1, wherein modulating the function of the neural fiberfurther comprises at least partially denervating the kidney.
 7. Themethod of claim 1, wherein modulating the function of the neural fiberfurther comprises inducing an effect in the neural fiber chosen from thegroup consisting of irreversible electroporation, electrofusion,necrosis, apoptosis, gene expression alteration, cytokine up-regulationalteration, and combinations thereof.
 8. The method of claim 1, whereinmodulating the function of the neural fiber further comprises thermallymodulating the function of the neural fiber.
 9. The method of claim 1,wherein modulating the function of the neural fiber further comprisesmodulating the function of the neural fiber with high frequencyultrasound.
 10. A method for treating end-stage renal disease, themethod comprising: modulating a function of a neural fiber thatcontributes to renal function of a kidney of a patient, whereinmodulating the function of the neural fiber further comprises modulatingthe function via a percutaneous approach.
 11. The method of claim 10,wherein modulating the function via a percutaneous approach furthercomprises modulating the function via a laparoscopic approach.
 12. Themethod of claim 10, wherein modulating the function via a percutaneousapproach further comprises modulating the function via an endoluminalapproach.
 13. The method of claim 10, wherein modulating the function ofthe neural fiber further comprises modulating the function of the neuralfiber via an electric field.
 14. The method of claim 13, whereinmodulating the function of the neural fiber via an electric fieldfurther comprises exposing the neural fiber to a pulsed electric field.15. The method of claim 13, wherein modulating the function of theneural fiber via an electric field further comprises exposing the neuralfiber to a stimulation electric field.
 16. The method of claim 10,wherein modulating the function of the neural fiber further comprisesdelivering a neuromodulatory agent to the neural fiber.
 17. The methodof claim 10, wherein modulating the function of the neural fiber furthercomprises at least partially denervating the kidney.
 18. The method ofclaim 10, wherein modulating the function of the neural fiber furthercomprises inducing an effect in the neural fiber chosen from the groupconsisting of irreversible electroporation, electrofusion, necrosis,apoptosis, gene expression alteration, cytokine up-regulationalteration, and combinations thereof.
 19. The method of claim 10,wherein modulating the function of the neural fiber further comprisesthermally modulating the function of the neural fiber.
 20. The method ofclaim 10, wherein modulating the function of the neural fiber furthercomprises modulating the function of the neural fiber with highfrequency ultrasound.